Batya Swift Yasgur
June 24, 2024
In October 2023, Robert Card — a grenade instructor in the Army Reserve — shot and killed 18 people in Maine, before turning the gun on himself. As reported by The New York Times, his family said that he had become increasingly erratic and violent during the months before the rampage.
A postmortem conducted by the Chronic Traumatic Encephalopathy (CTE) Center at Boston University, Boston, found “significant evidence of traumatic brain injuries” [TBIs] and “significant degeneration, axonal and myelin loss, inflammation, and small blood vessel injury” in the white matter, the center’s director, Ann McKee, MD, said in a press release. “These findings align with our previous studies on the effects of blast injury in humans and experimental models.”
Members of the military, such as Card, are exposed to blasts from repeated firing of heavy weapons not only during combat but also during training.
In 2022, the US Department of Defense (DOD) launched its Warfighter Brain Health Initiative with the aim of “optimizing service member brain health and countering traumatic brain injuries.”

What Is the Underlying Biology?
Snyder was the lead author of a white paper produced by the Alzheimer’s Association in 2018 on military-related risk factors for AD and related dementias. “There is a lot of work trying to understand the effect of pure blast waves on the brain, as opposed to the actual impact of the injury,” she told Medscape Medical News.
The white paper speculated that blast exposure may be analogous to subconcussive brain injury in athletes where there are no obvious immediate clinical symptoms or neurological dysfunction but which can cause cumulative injury and functional impairment over time.
Common Biomarker Signatures
A recent study in Neurology comparing 51 veterans with mild TBI (mTBI) with 85 veterans and civilians with no lifetime history of TBI is among the first to explore these biomarker changes in human beings.
“Our findings suggest that chronic neuropathologic processes associated with blast mTBI share properties in common with pathogenic processes that are precursors to Alzheimer’s disease onset,” co-author Elaine Peskind, MD, professor of Psychiatry and Behavioral Sciences, University of Washington, Seattle, told Medscape Medical News.

The largely male participants were a mean age of 34 years and underwent standardized clinical and neuropsychological testing as well as lumbar puncture to collect cerebrospinal fluid (CSF). The mTBI group had experienced at least one war zone blast or combined blast/impact that met criteria for mTBI, but 91% had more than one blast mTBI, and the study took place over 13 years.
For example, at age 50, they had lower mean levels of CSF amyloid beta 42 (Aβ42), the earliest marker of brain parenchymal Aβ deposition, compared with the control group (154 pg/mL and 1864 pg/mL lower, respectively).
High CSF phosphorylated tau181 (p-tau181) and total tau are established biomarkers for AD. However, levels of these biomarkers remained “relatively constant with age” in participants with mTBI but were higher in older ages for the non-TBI group.
In Alzheimer’s, a reduction in CSF Aβ42 may occur up to 20 years before the onset of clinical symptoms, according to Peskind. “But what we don’t know from this study is what this means, as total tau protein and p-tau181 in the CSF were also low, which isn’t entirely typical in the picture of preclinical Alzheimer’s disease,” she said. However, changes in total tau and p-tau181 lag behind changes in Aβ42.
Is Impaired Clearance the Culprit?
Co-author Jeffrey Iliff, PhD, professor, University of Washington Department of Psychiatry and Behavioral Sciences and University of Washington Department of Neurology, Seattle, elaborated.

“In the setting of Alzheimer’s disease, a signature of the disease is reduced CSF Aβ42, which is thought to reflect that much of the amyloid gets ‘stuck’ in the brain in the form of amyloid plaques,” he told Medscape Medical News. “There are usually higher levels of phosphorylated tau and total tau, which are thought to reflect the presence of tau tangles and degeneration of neurons in the brain. But in this study, all of those were lowered, which is not exactly an Alzheimer’s disease profile.”
Iliff, associate director for research, VA Northwest Mental Illness Research, Education, and Clinical Center at VA Puget Sound Health Care System, Seattle, suggested that the culprit may be impairment in the brain’s glymphatic system. “Recently described biological research supports [the concept of] clearance of waste out of the brain during sleep via the glymphatic system, with amyloid and tau being cleared from the brain interstitium during sleep.”
A recent hypothesis is that blast TBI impairs that process. “This is why we see less of those proteins in the CSF. They’re not being cleared, which might contribute downstream to the clumping up of protein in the brain,” he suggested.
In blast TBI, energy from the explosion and resulting overpressure wave are “transmitted through the brain, which causes tissues of different densities — such as grey and white matter — to accelerate at different rates,” according to Iliff. This results in the shearing and stretching of brain tissue, leading to a “diffuse pattern of tissue damage.”
It is known that blast TBI has clinical overlap and associations with posttraumatic stress disorder (PTSD), depression, and persistent neurobehavioral symptoms; that veterans with a history of TBI are more than twice as likely to die by suicide than veterans with no TBI history; and that TBI may increase the risk for AD and related dementing disorders, as well as CTE.
Iliff and his group previously found that glymphatic function is “markedly and chronically impaired” following impact TBI in mice and that this impairment is associated with the mislocalization of astroglial aquaporin 4 (AQP4), a water channel that lines perivascular spaces and plays a role in healthy glymphatic exchange.
In their new study, the researchers examined both the expression and the localization of AQP4 in the human postmortem frontal cortex and found “distinct laminar differences” in AQP4 expression following blast exposure. They observed similar changes as well as impairment of glymphatic function, which emerged 28 days following blast injury in a mouse model of repetitive blast mTBI.
And in a cohort of veterans with blast mTBI, blast exposure was found to be associated with an increased burden of frontal cortical MRI-visible perivascular spaces — a “putative neuroimaging marker” of glymphatic perivascular dysfunction.
The earlier Neurology study “showed impairment of biomarkers in the CSF, but the new study showed the ‘why’ or ‘how’ these biomarkers are impaired, which is via impairment of the glymphatic clearance process,” Iliff explained.
Veterans Especially Vulnerable
Peskind, co-director of the VA Northwest Mental Illness Research, Education and Clinical Center, VA Puget Sound Health Care System, noted that while the veterans in the earlier study had at least one TBI, the average number was 20, and it was more common to have more than 50 mTBIs than to have a single one.
The Maine shooter, Card, had not seen combat and was not assessed for TBI during a psychiatric hospitalization, according to The New York Times.
Peskind added that this type of blast damage is likely specific to individuals in the military. “It isn’t the sound that causes the damage,” she explained. “It’s the blast wave, the pressure wave, and there aren’t a lot of other occupations that have those types of occupational exposures.”
Snyder hopes that the researchers will follow the participants in the Neurology study and continue looking at specific markers related to AD brain changes. What the research so far shows “is that, at an earlier age, we’re starting to see those markers changing, suggesting that the underlying biology in people with mild blast TBI is similar to the underlying biology in Alzheimer’s disease as well.”
Michael Alosco, PhD, associate professor and vice chair of research, Department of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, called the issue of blast exposure and TBI “a very complex and nuanced topic,” especially because TBI is “considered a risk factor of Alzheimer’s disease” and “different types of TBIs could trigger distinct pathophysiologic processes; however, the long-term impact of repetitive blast TBIs on neurodegenerative disease changes remains unknown.”

He co-authored an editorial on the earlier Neurology study that noted its limitations, such as a small sample size and lack of consideration of lifestyle and health factors but acknowledged that the “findings provide preliminary evidence that repetitive blast exposures might influence beta-amyloid accumulation.”
Clinical Implications
For Peskind, the “inflection point” was seeing lower CSF Aβ42, about 20 years earlier than ages 60 and 70, which is more typical in cognitively normal community volunteers.
But she described herself as “loath to say that veterans or service members have a 20-year acceleration of risk of Alzheimer’s disease,” adding, “I don’t want to scare the heck out of our service members of veterans.” Although “this is what we fear, we’re not ready to say it for sure yet because we need to do more work. Nevertheless, it does increase the index of suspicion.”
Common comorbidities with TBI are PTSD and obstructive sleep apnea (OSA), which can also cause cognitive issues and are also risk factors for dementia.
Iliff agreed. “If you see a veteran with a history of PTSD, a history of blast TBI, and a history of OSA or some combination of those three, I recommend having a higher index of suspicion [for potential dementia] than for an average person without any of these, even at a younger age than one would ordinarily expect.”
Peskind recommended asking patients, “Do they snore? Do they thrash about during sleep? Do they have trauma nightmares? This will inform the type of intervention required.”
Alosco added that there is no known “safe” threshold of exposure to blasts, and that thresholds are “unclear, particularly at the individual level.” In American football, there is a dose-response relationship between years of play and risk for later-life neurological disorder. “The best way to mitigate risk is to limit cumulative exposure,” he said.
The study by Li et al was funded by grant funding from the Department of Veterans Affairs Rehabilitation Research and Development Service and the University of Washington Friends of Alzheimer’s Research. Other sources of funding to individual researchers are listed in the original paper. The study by Braun et al was supported by the National Heart, Lung and Blood Institute; the Department of Veterans Affairs Rehabilitation Research and Development Service; and the National Institute on Aging. The white paper included studies that received funding from numerous sources, including the National Institutes of Health and the US Department of Defense. Iliff serves as the chair of the Scientific Advisory Board for Applied Cognition, Inc., from which he receives compensation and in which he holds an equity stake. In the last year, he served as a paid consultant to the company Gryphon Biosciences. Peskind has served as a paid consultant to the companies Genentech, Roche, and Alpha Cognition. Alosco was supported by grant funding from the NIH; he received research support from Rainwater Charitable Foundation, Inc., and Life Molecular Imaging, Inc.; he has received a single honorarium from the Michael J. Fox Foundation for services unrelated to this editorial; and he also received royalties from Oxford University Press, Inc. The other authors’ disclosures are listed in the original papers.
Batya Swift Yasgur, MA, LSW, is a freelance writer with a counseling practice in Teaneck, New Jersey. She is a regular contributor to numerous medical publications, including Medscape Medical News and WebMD, and is the author of several consumer-oriented health books as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom (the memoir of two brave Afghan sisters who told her their story).